I. Introduction
The sense of smell has been used in medicine for thousands of years, from early Greek and Chinese practitioners to modern clinicians (see, Hayden et al., Post grad. Med., 67:110-118 (1980); Kerr et al., Trends in Microbiology, 9:59 (2001); Saini et al., Biologist, 48:229-233 (2001)). However, smell has not been utilized for routine diagnostic purposes, perhaps due to the subjective nature of human odor recognition as well as the possibly complex biological origins of chemical signatures that constitute a “medical odor.”
Recent advances in odor sensing technology, signal processing and diagnostic algorithms have created chemical sensing and identification devices called “electronic noses” (see, Kerr et al., Trends in Microbiology, 9:59 (2001)). The electronic nose has been used for several years in a wide variety of industrial and commercial applications. In the laboratory, these devices have been shown to differentiate bacterial cultures (see, Kerr et al., Sniffing out Infection, Trends in Microbiology, 9, 59, (2001); Saini et al., Biologist, 48, 229-233, (2001).
Multiple groups have used electronic nose technology for recognition of disease in vivo (see, Martini A et al., Critical Reviews in Biomedical Engineering, 28:481-485 (2000)). In veterinary science, an electronic nose device was used to identify dietary ketosis in dairy cattle from breath measurement. In medicine, applications have been reported that range from the detection of pneumonia to differentiation of serum from cerebrospinal fluid (see, Dr. E. Thaler, Univ. Penn. Hospital, personal communication (2001); Hanson et al., The use of a novel ‘electronic nose’ to diagnose the presence of intrapulmonary infection. Anesthesiology, 87, A269 (1997). Recently, the potential use of the electronic nose as a screening tool was demonstrated for bacterial vaginosis and urinary tract infection (see, Chandiok, et al., Screening for Bacteria Vaginosis: A Novel Application of Artificial Nose Technology, J. Clin. Pathol. 50:790-791 (1997); Aathithan et al. Diagnosis of Bacteriuria by Detection of Volatile Organic Compounds in Urine Using an Automated Headspace Analyzer with Multiple Conducting Polymer Sensors, J. Clin. Microbiol. 39:2590-2593 (2001).
As described above, electronic noses are currently being used to diagnose disease by identification of marker gases from particular microorganisms. However, it would be useful to diagnose a disease or condition based on the presence of a collection of odorants, (“smellprint”) or a volatile chemical signature, rather than one specific odorant. Such a method would allow for rapid and accurate detection of any disease associated with a particular “smellprint.” In particular, the method would be useful for screening for diseases with complex presentations and diseases where diagnosis is slow and problematic, such as ventilator-associated pneumonia and sinusitis. The method would also be useful for monitoring diseases and conditions in real time.
II. Medical Applications
A. Ventilator-Associated Pneumonia
Nosocomial pneumonia (NP) is the second most common nosocomial infection in the U.S. with an incidence of 5-10 per 1000 hospital admissions. It has the highest morbidity and mortality of the nosocomial infections tracked by the Centers for Disease Control, and the diagnosis is associated with the prolongation of hospital stays by 7-9 days. The crude mortality rate for nosocomial pneumonia (NP) may be as high as 70%.
The incidence of NP increases by 6-20 fold in mechanically ventilated patients. Ventilator associated pneumonia (VAP) is defined as a parenchymal lung infection occurring greater than 48 hours after initiation of mechanical ventilation. It occurs in 10-25% of patients intubated for longer than 48 hours, and it is the most common associated infection in intensive care patients according to some studies (see, C. W. Hanson, Pneumonia. “In: M. J. Murray et al (eds.), Critical Care Medicine: Perioperative Management, 2nd Ed. Lippincott, Williams & Wilkins, Philadelphia” (2002)). VAP has an associated mortality rate of 25-70%. The risk of VAP increases with increased duration of mechanical ventilation.
Survival rates improve with appropriate treatment, but the diagnosis of pneumonia in the ICU patient is difficult and most tests are invasive, requiring sampling devices of varying complexity to be inserted into the lungs. Signs and symptoms of infection in this population can have multiple causes. Radiographic evidence of pneumonia can be mimicked by other conditions. Culture results have a high rate of false-negatives after the administration of antibiotics. In addition, regardless of whether the patient is being treated with antibiotics, culture results are often mixed or inconclusive due to threshold criteria for pathogen identification. Further compounding the problem is the variability in threshold criteria between labs. Due to the difficulty of diagnosing bacterial pneumonia, the Clinical Pulmonary Infection Score (CPIS) has become an “accepted standard” (see, Pugin et al., American Review of Respiratory Disease, 143(5 Pt 1):1121-9 (1991)). The CPIS score is a cumulative score developed from several individual measures that include temperature, white cell count, secretion amount and character, pulmonary function (PaO2/FIO2 ratio), chest radiograph infiltrates and tracheal aspirate culture.
An electronic nose can aid in the rapid and accurate diagnosis and treatment of ventilator-associated pneumonia, potentially reducing morbidity and mortality in this population, as well as containing and reducing hospital costs incurred by testing and increased length of hospital stay.
B. Sinusitis
Acute and chronic sinusitis together make up the most commonly used ICD9 code in the United States, surpassing both hypertension and atherosclerosis. Sixty-six million adults, fully 35% of the adult U.S. population, report having sinusitis or sinus problems at least once during the previous 12 months (Dr. E. Thaler, “Univ. Penn. Hospital, personal communication” (2001)). Sinusitis is the most frequently reported chronic condition, affecting 14.1% of the U.S. population.
However, the diagnosis of sinusitis can be difficult to make, as it may be confused with various other nasal conditions. The best means of securing the diagnosis is by identification of bacterial pathogens upon culture of the involved sinuses. Studies have shown that 70% of acute sinusitis cases are caused by Streptococcus pneumoniae and Haemophilus influenzae in adults and children. Other species, including Moraxella catarrhalis and Staphylococcus aureus, are also significant contributors to acute sinusitis. The problem with this method of diagnosis is that it takes 48 hours to identify the bacteria on culture, and takes further time to determine antibiotic susceptibility. In addition, the presence of normal oralpharyngial flora may confound the results.
An electronic nose would assist physicians in determining which patients require further testing, i.e., microbiological culture, and which do not. Effective screening could reduce the number of negative samples sent for microbiological culture and the number of prescriptions for broad-spectrum antibiotics, thereby reducing the drug resistance of bacteria. Rapid identification of the predominant bacterial species responsible for sinus infection in patients would provide a guide for physicians in choosing antibiotics in real time, along the lines of the rapid strep test used for acute pharyngitis.
Thus it is clear that there is a need for methods and devices that diagnose disease or a condition by detecting a multiple-component “smellprint” associated with the disease or a condition. Such methods allow for rapid (within the hour) diagnosis of disease and monitoring of disease in real time. The present invention fulfills this and other needs.